PROJECT ABSTRACT This is an application for a K23 Career Development Award for Catherine A. Bonham, MD who is an immunologist and a pulmonary critical care physician at the University of Chicago. She is building a career as a translational immunologist-pulmonologist, capable of bringing cutting edge immunology from the bench to the bedside to understand the interaction of the immune system with the development of pulmonary fibrosis. This K23 award will provide Dr. Bonham with the support necessary to achieve the following goals: 1) develop advanced immunology expertise for understanding immune dysregulation associated with idiopathic pulmonary fibrosis (IPF) progression and mortality; 2) develop biostatistical expertise in the analysis of biospecimen and clinical data collected longitudinally from patients with IPF, and 3) gain new skills and expertise in T cell metabolism alterations in hypoxia. To achieve these goals, Dr. Bonham has assembled a mentoring team led by primary mentor, Dr. Anne Sperling, who is a pulmonary immunologist with experience in human blood and tissue immunology, with co-mentors Dr. Gokhan Mutlu, who is Section Chief of Pulmonary Critical Care with expertise in cellular metabolism and IPF, and Dr. Matthew Churpek, a pulmonologist and PhD biostatistical expert. The proposed research will be conducted at the University of Chicago, one of the nation's leading private universities and home to renowned divisions of immunology, pulmonary medicine, and biostatistics, with state-of-the-art facilities to enable cutting-edge research. IPF remains a deadly disease with few treatment options and none that are curative. One of the most challenging and poorly understood features of IPF is the inhomogeneity of disease progression and hence variable quality of life and survival outcomes. Individualized prognostication and treatment plans are thus not truly possible; in addition, the variability of disease course can make selection of endpoints for clinical trials challenging. Genomic studies that analyze stable versus rapidly progressive IPF patients have repeatedly shown significant associations with immune system pathways, though the role of the immune system in IPF has been historically controversial. Dr. Bonham's preliminary data indicates that long-term IPF survivors with preserved lung function highly express two distinct costimulatory molecules on circulating CD4+ T cells, CD28 and Inducible Costimulator (ICOS). Dr. Bonham's central hypothesis is that IPF patients with ICOS high CD4+ T cells have preserved effector memory T cell differentiation, and cytokine production that is responsive to hypoxia and resistant to IPF progression. In her aims she will systematically examine the effector functions of ICOShi cells and how circulating CD4+ T cell ICOS expression reflects altered tissue resident T cell phenotypes and effector functions. Finally, she will determine how T cell costimulation and effector function is modulated by IPF tissue hypoxia.